Development of CD46 theranostics for imaging and treatment of multiple myeloma

项目摘要和摘要 这项提议的主要目标是开发以CD46为靶点的新型治疗药物，用于成像和治疗 多发性骨髓瘤(MM)。CD46是一种新的治疗靶点，具有同源抗体-药物结合物FOR46， 目前正在进行第一阶段的临床试验。我们的初步数据显示CD46在MM中高表达。 我们开发并实现了[89Zr]DFO-YS5和[225Ac]DOTA-YS5作为靶向成像和治疗药物 这个提议的中心假设是CD46是分子成像和治疗的有效靶点。 在这项建议中，我们在临床前模型和MM患者的初步研究中检验了这一假设。 为了验证这一假设，我们组建了一个由化学家、生物学家、成像专家组成的经验丰富的团队 科学家、物理学家和内科医生在临床前模型和患者中评估这种方法。以特定的目标 1，我们将开发[89Zr]DFO-YS5和[225Ac]DOTA-YS5作为MM的PET成像和治疗剂。 具体目标2，我们将开发新的共同治疗方法来最大化CD46的表达，并利用这些方法 增加[89Zr]DFO-YS5PET和[225Ac]DOTA-YS5处理。在目标3中，我们进行了中试的[89Zr]DFO-YS5 PET 对多发性骨髓瘤患者进行影像研究，并对数据进行分析，确定其对发现病变部位的敏感性。 本提案中开发的方法最终将用于开发新的诊断和治疗方法 治疗多发性骨髓瘤的方法，以帮助降低这种疾病的发病率和死亡率。

PROJECT SUMMARY AND ABSTRACT The primary goal of this proposal is to develop novel theranostic agents targeting CD46 for imaging and treatment of multiple myeloma (MM). CD46 is a novel therapeutic target, with a cognate antibody-drug conjugate, FOR46, now in phase 1 clinical trials. Our preliminary data demonstrate high expression of CD46 in MM. In this proposal, we develop and implement [89Zr]DFO-YS5 and [225Ac]DOTA-YS5 as imaging and therapeutic agents targeting MM. The central hypothesis of this proposal is that CD46 is an effective target for molecular imaging and therapy of MM. In this proposal we test this hypothesis in preclinical models, and in a pilot study of patients with MM. In order to test this hypothesis, we have assembled an experienced team of chemists, biologists, imaging scientists, physicists, and physicians to evaluate this method in preclinical models and in patients. In specific aim 1, we will develop [89Zr]DFO-YS5 and [225Ac]DOTA-YS5 as PET imaging and therapeutic agents for MM. In specific aim 2, we will develop new co-treatment approaches to maximize CD46 expression, and use these to augment [89Zr]DFO-YS5 PET and [225Ac]DOTA-YS5 treatment. In aim 3, we perform a pilot [89Zr]DFO-YS5 PET imaging study in patients with MM, and analyze the data to determine its sensitivity for detecting sites of disease. The methods developed in this proposal will ultimately be used to develop novel diagnostic and therapeutic approaches in MM, to help reduce morbidity and mortality for this disease.